Single carbon precursor synthons

ABSTRACT

The chemistry of [ 13 C]methyl phenyl sulfide is exploited to produce new isotopically labeled precursors that allow for the facile assembly of a wide range of labeled molecules from simple and relatively inexpensive starting materials. These compounds are applicable to a variety of research areas such as quantum computing, metabolism and materials science.

CROSS REFERENCE TO RELATED APPLICATIONS

This patent application claims the priority and benefit of two U.S. Provisional Patent Applications the first being No. 60/923,107 filed Apr. 11, 2007 entitled “Carbon Labeled, Isotopically Labeled C13 Molecules and also deuterium Labeled Molecules Based on the Chemistry of C13 Methyl Phenyl Sulfide” and the second being No. 60/948,359 filed Jul. 6, 2007 and titled “Synthesis of Isotopically Tagged Synons”. Both 60/923,107 and 60/948,359 are herein incorporated by reference.

TECHNICAL FIELD

The present invention relates to labeled compounds and more particularly to compounds derived from isotopically enriched Alkoxy[¹³C]methyl phenyl sulfone or Alkoxy[¹⁴C]methyl phenyl sulfone. As such, the isotopic tags can be carbon-13 or carbon-14.

BACKGROUND OF THE INVENTION

Phenyl sulfones are extremely useful for the synthesis of many important biochemicals and pharmaceuticals. Additionally, the use of stable isotopes has long been considered to be a promising tool in biomedical diagnosis. Furthermore, the past two decades have seen a tremendous leap forward in the development of very sophisticated instrumentation for the detection of disease and for probing biological structure and function. In conjunction with this a need for very complicated isotopically labeled materials has been on the increase.

Another area of application has become critical after the “9/11” tragedies. The use of stable isotopes in molecules (metabolites) for the rapid detection of threat agents (chemical and biological) is now in large demand. Current isotopic labeling precursors and techniques, however, have made this a very daunting task.

In order to meet the urgent and growing demand, high purity isotopically labeled compounds are needed.

BRIEF SUMMARY

The following summary is provided to facilitate an understanding of some of the innovative features unique to the embodiments and is not intended to be a full description. A full appreciation of the various aspects of the embodiments can be gained by taking the entire specification, claims, drawings, and abstract as a whole.

It is therefore an aspect of the embodiments to exploit the chemistry of [¹³C]methyl phenyl sulfide to produce new isotopically labeled precursors that allow for the facile assembly of a wide range of labeled molecules from simple and relatively inexpensive starting materials. These compounds are applicable to a variety of research areas such as quantum computing, metabolism and materials science.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying figures, in which like reference numerals refer to identical or functionally similar elements throughout the separate views and which are incorporated in and form a part of the specification, further illustrate aspects of the embodiments and, together with the background, brief summary, and detailed description serve to explain the principles of the embodiments.

FIG. 1 illustrates producing Chloro[¹³C]methyl phenyl sulfide, dichloro[¹³C]methyl phenyl sulfide and trichloro[¹³C]methyl phenyl sulfide in accordance with aspects of the embodiments;

FIG. 2 illustrates the general structures of Chloro[¹³C]methyl phenyl sulfide, dichloro[¹³C]methyl phenyl sulfide, trichloro[¹³C]methyl phenyl sulfide and other closely related compounds in accordance with aspects of the embodiments;

FIG. 3 illustrates producing Alkoxy[¹³C]methyl Phenyl Sulfide and (Phenylthio)(alkylthio)[¹³C]methane in accordance with aspects of the embodiments;

FIG. 4 illustrates the general structures of Alkoxy[¹³C]methyl Phenyl Sulfide, (Phenylthio)(alkylthio)[¹³C]methane and other closely related compounds in accordance with aspects of the embodiments;

FIG. 5 illustrates the oxidation of alkoxy[¹³C]methyl phenyl sulfide in accordance with aspects of the embodiments;

FIG. 6 illustrates the oxidation of (Arylthio)(alkylthio)[¹³C]methane in accordance with aspects of the embodiments;

FIG. 7 illustrates the general structures of alkoxy[¹³C]methyl phenyl sulfide, (Arylthio)(alkylthio)[¹³C]methane and other closely related compounds in accordance with aspects of the embodiments;

FIG. 8 illustrates the reactions of dichloro[¹³C]ethyl phenyl sulfide in accordance with aspects of the embodiments;

FIG. 9 illustrates the reactions of trichloro[¹³C]methyl phenyl sulfide in accordance with aspects of the embodiments;

FIG. 10 illustrates the synthesis of 1-[(phenylthio)[¹³C]methyl]-2,5-Pyrrolidinedione in accordance with aspects of the embodiments; and

FIG. 11 illustrates the general structures of 1-[(phenylthio)[¹³C]methyl]-2,5-Pyrrolidinedione and other closely related compounds in accordance with aspects of the embodiments.

DETAILED DESCRIPTION

The following description contains a series of examples wherein previously known labeled compounds are processed to yield highly pure labeled compounds that are not previously known.

Synthesis of dichloro[¹³C]methyl phenyl sulfide

A sample of [¹³C]-Methyl phenyl sulfide (91.3%, 6.3 g, 0.046 mol, 1 equivalent) was dissolved in thiophene-free benzene (50 mL) in a 250 mL round bottom flask, flushed with argon and was cooled using an ice-water bath. Once the benzene began to freeze, N-chlorosuccinimide (13.08 g, 0.098 mol, 2.1 eq) was added in a single portion while stirring rapidly. The reaction mixture was permitted to warm to room temperature slowly as the ice bath melted, while stirring under argon. After 24 hours, the reaction was found to be complete by ¹³C NMR by taking an aliquot from the reaction mixture, dissolving it into COCl₃, and monitoring the disappearance of [¹³C]-methyl phenyl sulfide (δ=16.9 ppm) and subsequent appearance of the desired dichloro-[¹³C]-methyl phenyl sulfide (δ=76.0 ppm). The reaction mixture was then filtered to remove succinimide, the solids were washed with benzene and volatiles were removed by vacuum. The resulting oil contained some succinimide and this oil and precipitate were partitioned between water and dichloromethane in order to remove the remaining succinimide. The organic layer was washed with water (100 mL, 2×) filtered through cotton, and volatiles again removed by vacuum to give a quantitative yield of clear pale yellow liquid which was used without further purification.

The spectra data are as follows:

¹H NMR (CDCl₃, 300 MHz): δ=7.45-7.59 (m, 3H), 7.79 (d, 2H)

¹³C NMR (CDCl₃, 75 MHz): δ=98.9 (¹³CCl₃), 129.5 (ArC-3), 130.9 (d, ²J_(CC)=3.3 Hz, ArC-1), 131.9 (d, ³J_(CC)=2.2 Hz, ArC-2), 137.5 (ArC-4)

Synthesis of trichloro[¹³C]methyl phenyl sulfide

A sample of [¹³C]-Methyl phenyl sulfide (91.3%, 28.8 g, 0.210 mol. 1 equivalent) was dissolved in thiophene-free benzene (350 mL) in a two liter Morton Flask, flushed with argon and was cooled using an ice-water bath. Once the benzene began to freeze, N-chlorosuccinimide (103 g, 0.771 mol. 3.7 eq) was added over a period of 7 minutes, via spatula as quickly as possible. The reaction mixture was gradually allowed to come to room temperature and stirred for 24 hours under argon. After 24 hours, the reaction was found to be complete by ¹³ NMR by taking an aliquot from the reaction mixture, dissolving it into CDCl₃, and monitoring the disappearance of [¹³C]-methyl phenyl sulfide (δ=16.9 ppm) and subsequent appearance of the desired trichloro-[¹³C]-methyl phenyl sulfide (δ=98.9 ppm). The reaction mixture was then filtered to remove succinimide, the solids were washed with benzene and volatiles were removed by vacuum. The resulting oil contained some succinimide and this oil and precipitate were partitioned between water and dichloromethane in order to remove the remaining succinimide. The organic layer was washed with water (300 mL, 2×) filtered through cotton, and volatiles again removed by vacuum to give a quantitative yield of colorless, low-melting crystalline solid that was suitable for single crystal x-ray analysis. A single crystal x-ray structure was determined for this compound.

The spectra data are as follows:

¹H NMR (CDCl₃, 300 MHz): δ=7.45-7.59 (m, 3H), 7.79 (d, 2H)

¹³C NMR (CD)Cl₃, 75 MHz): δ 98.9 (¹³CCl₃), 129.5 (ArC-3), 130.9 (d, ²J_(CC)=3.3 Hz, ArC-1), 131.9 (d, ³J_(CC)=2.2 Hz, ArC-2), 137.5 (ArC-4)

Synthesis of Ethoxy [¹³C]methyl phenyl sulfide

Chloro[¹³C]methyl phenyl sulfide (12.0 g, 0.075 mol) and ethyl alcohol (120 mL, 100%) were placed in a 250 mL round bottom flask equipped with a magnetic stir bar and a rubber septum. This mixture was sonicated at 40° C. for 6 hrs and then allowed to stir overnight at room temperature without sonication. After this period, ¹³CNMR analysis showed the complete disappearance of the starting material at 51 ppm and the quantitative formation of the desired product at 74 ppm. The reaction mixture was then transferred to a separatory funnel containing dichloromethane (120 mL) and DI water (100 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered and then concentrated in vacuo to afford 12.46 g (98.2%) of the titled compound as a pale yellow fluid. The crude product was sufficiently pure and was used in the next reaction without further purification.

The spectra data are as follows:

¹HNMR (300 MHz in CDCl₃ with 0.03% TMS) δ: 7.48-7.18 (5H, m), δ: 5.23, 4.70 (2H, d J 158.1) δ: 3.68, 3.67, 3.66, 3.65, 3.63, 3.62, 3.61, 3.60 (2H, qd J 6.98, 3.67) δ: 1.23, 1.19, 1.18 (3H, t J 6.99). ¹³CNMR (75 MHz in CDCl₃) δ: 136.398, 130.23, 129.00, 126.71, 74.70, 63.93, and 15.80; Mass spectra m/e 169 (M+.), 124, 109, and 60.

Synthesis of ethoxy [¹³C]methyl phenyl sulfoxide

A sample of ethoxy [¹³C]methyl phenyl sulfide (10 g, 0.059 moles) was dissolved in ethanol (100 mL) and hydrogen peroxide (30% by wt., 13.4 mL, 0.118 moles) was added. The reaction was stirred for 24 hours at ambient temperature. The product was extracted with dichloromethane (3×100 mL). The dichloromethane layer was washed with water (3×100 mL) until the aqueous portion tested negative to KI starch paper. The product was suitable for use in subsequent reactions without purification.

The spectra data are as follows:

¹HNMR (300 MHz in CDCl₃ with 0.03% TMS)/δ: 7.95-7.55 (m 5H), δ: 4.81, 4.30 (d J 154.43 ¹³CH₂); δ: 3.93, 3.91, 3.89, 3.90, 3.89, 3.87, 3.86, 3.85, 3.84 (qd J 6.99, 3.31 —OCH₂) δ: 1.21, 1.19, 1.16 (t J 6.99). ¹³CNMR (75 MHz in CDCl₃) δ: 134.99, 134.20, 129.36, 128.97 δ: 86.43 (s, ¹³ CH₂) δ: 69.53, (—OCH₂), and 15.20 (CH₃).

Synthesis of ethoxy [¹³C]methyl phenyl sulfoxide

An oxone solution (prepared by dissolving 163.69 g of oxone in 720 ml deionized water) was added to an ice-cooled solution of ethoxy [¹³C]-methylphenyl sulfide (16.0 g, 0.095 mol) in ethyl acetate-ethanol (1:1, 150 mL). This reaction mixture was allowed to stir at 0° C. for 30 mins and ¹³CNMR in CDCl₃ at that point showed a quantitative formation of the desired product peak at 86 ppm. The reaction mixture was poured into a 2-L separatory funnel containing dichloromethane (300 mL) and deionized water (350 mL). The organic layer was separated and washed with deionized water (3×150 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and then concentrated in vacuo to afford 18.4 g, (96.7%) of the titled compound as pale yellow fluid pure enough for the next reaction.

The spectra data are as follows:

¹HNMR (300 MHz in CDCl₃ with 0.03% TMS)/δ: 7.95-7.55 (m 5H), δ: 4.81, 4.30 (d J 154.43 ¹³CH₂); δ: 3.93, 3.91, 3.89, 3.90, 3.89, 3.87, 3.86, 3.85, 3.84 (qd J 6.99, 3.31 —OCH₂) δ: 1.21, 1.19, 1.16 (t J 6.99). ¹³CNMR (75 MHz in CDCl₃) δ: 134.99, 134.20, 129.36, 128.97 δ: 86.43 (s, ¹³ CH₂) δ: 69.53, (—OCH₂), and 15.20 (CH₃).

Synthesis of ethyl-[¹³C]-formate

Dichloro-[¹³C]-methyl phenyl sulfide (20.2 g, 0.104 mol, 1 equivalent) was dissolved in ethanol (absolute, 200 mL) in a 1 L round bottom flask. The reaction vessel was loosely sealed with a polyethylene cap and permitted to stir at room temperature. After five days, the reaction was found to be complete by ¹³C NMR by taking an aliquot from the reaction solution, dissolving it into CDCl₃, and monitoring the disappearance (to within 2% remaining) of dichloro-[¹³C]-methyl phenyl sulfide (δ=76.0 ppm) and subsequent appearance of the desired ethyl-[¹³C]-formate (δ=161.0 ppm). The reaction solution was then washed with aqueous saturated sodium bicarbonate (200 mL, 2×). The layers were separated and the organic layer was washed with 0.1N aqueous sodium hydroxide (200 mL, 1×). The layers were separated and the organic layer was then distilled using a simple distillation apparatus to yield a colorless liquid which was used without further purification.

Synthesis of Diethyl[¹³C]carbonate

Trichloro-[¹³C]-Methyl phenyl sulfide (7.7 g, 0.0333 mol, 1 equivalent) was dissolved in ethanol (absolute, 77 mL) in a 500 mL round bottom flask. The reaction solution was then stirred at room temperature. After six days the reaction was determined to be 85% complete by ¹³C NMR by taking an aliquot from the reaction solution, dissolving it into CDCl₃, and monitoring the disappearance of trichloro-[¹³C]-methyl phenyl sulfide (δ=98.9 ppm) and subsequent appearance of the desired diethyl-[¹³C]-carbonate (δ=155.2 ppm). The reaction was then placed in a warming bath (45° C.). After an additional 24 hours, the reaction was found to be complete by ¹³C NMR using the method described above. The reaction solution was poured into dichloromethane (80 mL) and then washed with aqueous saturated sodium bicarbonate (80 mL). The layers were separated and the organic layer was then washed with 0.1N aqueous sodium hydroxide (150 mL 2×). At this time, ¹³C NMR showed no ethanol or thiophenol in the product. The organic layer was then placed onto a rotary evaporator and dichloromethane was removed (P=150 torr, T=25° C.) to yield a colorless liquid that still contained 50% dichloromethane.

Synthesis of [¹³C]guanidine hydrochloride

Ethanol (absolute, 230 mL) was placed into a 1 L round bottom flask with a stir bar. The round bottom flask was then attached to an argon manifold fitted with an oil bubbler in order to maintain slight positive pressure. The round bottom flask was then placed into a methanol bath equipped with a Cryocool immersion chiller. The bath was cooled to −80° C. while maintaining positive pressure on the inert gas manifold, as determined by the oil bubbler. Once the desired temperature was attained, the argon line was disconnected and a fritted glass tube connected to an anhydrous ammonia tank was introduced below the surface of the cold ethanol. Ammonia was dissolved in the cold ethanol by bubbling it through the fritted glass for one-half hour while stirring. The fritted glass tube was then removed from the flask. The reaction vessel was reattached to the argon line, removed from the cold methanol bath and permitted to warm gradually. Once the temperature had reached −15° C. (checked by IR thermometer) ammonium hydroxide (29.9% aqueous sol'n, 60 mL, to make 20% water by volume) was added to the ethanolic solution of ammonia while stirring. Trichloro-[¹³C]-methyl phenyl sulfide (21.81 g, 0.0954 mol, 1 equivalent) was dissolved in dichloromethane (60 mL) in order to aid its solubility in the cold polar solution. When the internal temperature had raised to −5° C. the trichloro-[¹³C]-methyl phenyl sulfide solution was added at once via syringe to the stirring ammonia solution. The reaction mixture was allowed to come to room temperature and stirred for three days under argon. After three days, the solution had turned dark red, and the reaction was found to be complete by ¹³C NMR by taking an aliquot from the reaction mixture, partitioning it between D₂O and CDCl₃, and monitoring the disappearance trichloro-[¹³C]-methyl phenyl sulfide (δ=98.9 ppm relative to CDCl₃) in the organic layer and subsequent appearance of the desired guanidine-¹³C hydrochloride (δ=158 ppm relative to ethanol).

In order to remove excess ammonia, argon was bubbled through the rapidly stirring solution using a Pasteur pipette attached to the manifold in order to deliver the stream of argon, All volatiles were removed by rotary evaporator followed by hi-vac to yield a dark brown/black solid. The solid was partitioned between water (100 mL) and dichloromethane (100 mL). The aqueous layer was washed with dichloromethane (3×100 mL) and then water was removed via rotary evaporator followed by hi-vac to yield a very dark solid (20.75 g). The dark solid was chromatographed on AG 50W X8 (hydrogen form, 100 g) cation exchange resin using 1N HCl followed by 2N HCl as the eluent system. The progress of the separation was monitored by taking aliquots directly from the column, placed directly into an NMR tube without lock solvent, and checking each aliquot for the appearance of a ¹³C signal by running an unlocked NMR experiment. Once a signal appeared, authentic urea-¹³C (δ=163 ppm) was added as a standard for comparison. Urea-13C co-eluted with ammonium chloride as the first fraction, which was eluted using 1N HCl. The eluent was changed to 2N HCl once the signal for urea-¹³C disappeared. Guanidine-¹³C hydrochloride (δ=158 ppm) appeared as the second fraction. The aqueous acid was removed from the fractions first using a rotary evaporator, and then dried using hi-vac with a nitrogen trap. The first fraction was then washed with cold ethanol and filtered to remove the ammonium chloride. The ethanol was removed using rotary evaporator followed by hi-vac to give urea-¹³C as a very pale yellowish solid (2.9 g, 0.047 mol, 49%). The second fraction gave guanidine-¹³C hydrochloride as a pale tan solid (4.3 g, 0.0446 mol, 47%) which was used without further purification.

The spectra data are as follows:

¹H NMR (D₂O, 300 MHz): δ=NA

¹³C NMR (D₂O, 75 MHz): δ 158.

Synthesis of Synthesis of 1-[(phenylthio)[¹³C]methyl]-2,5-Pyrrolidinedione

Succinimide (0.74 g, 0.0075 moles) was dissolved ethanol (8 mL) which contained sodium hydroxide (0.30 g, 0.0075 moles). This solution was stirred for 30 minutes and then the ethanol was removed by evaporation. To the resulting solid was suspended into acetonitrile (15 mL). To this mixture chloro[¹³C]methyl phenyl sulfide (1.19 g, 0.0075 moles) and the reaction was stirred at room temperature until complete. After 3 days the reaction was worked-up by the addition of water followed by extraction with dichloromethane (3×50 mL). The organic layer was dried over sodium sulfate, evaporated in vacuo to give the crude product. The product was purified by column chromatography.

The spectra data are as follows:

¹HNMR (300 MHz in CDCl₃ with 0.03% TMS)/δ: 7.49-7.26 (m 5H), δ: 4.83 (d, J=155.49 ¹³CH ₂, 2H); δ: 2.65 (s, CH ₂CH ₂, 4H)

¹³CNMR (75 MHz in CDCl₃) δ: 136.0, 132.43, 129.32, 128.14 δ: 86.43, 42.39 (s, ¹³ CH₂) δ: 28.19, (CH₂ CH₂).

The embodiments of the invention in which an exclusive property or right is claimed are defined as follows. 

1. A labeled compound having the structure:

wherein Z¹ is selected from the group consisting of H, alkyl, O-alkyl, S-alkyl, Cl, Br, and I; wherein Z¹ is selected from the group consisting of H, alkyl, O-alkyl, S-alkyl, Cl, Br, and I; wherein Z³ is selected from the group consisting of H, alkyl O-alkyl, -alkyl, Cl, Br, and I; wherein Z⁴ is selected from the group consisting of H, alkyl, O-alkyl, S-alkyl, Cl, Br, and I; wherein Z⁵ is selected from the group consisting of H, alkyl, O-alkyl, S-alkyl, Cl, Br, and I; wherein R¹ is selected from the group consisting of Cl, Br, I, H and ²H; wherein R² is selected from the group consisting of Cl, Br, I, H and ²H; and wherein R³ is selected from the group consisting of Cl, Br, I, —O-alkyl, —S-alkyl, H and ²H.
 2. The labeled compound of claim 1 having the structure:

wherein Ph is Phenyl.
 3. The labeled compound of claim 2 wherein R³ is —O-alkyl; R² is H; and R¹ is H.
 4. The labeled compound of claim 2 wherein R³ is —S-alkyl; R² is H; and R¹ is H.
 5. The labeled compound of claim 1: wherein R¹ is selected from the group consisting of H and ²H; wherein 12 is selected from the group consisting of H and ²H; and wherein R³ is selected from the group consisting of H₇Br, and I.
 6. The labeled compound of claim 1: wherein R¹ is selected from the group consisting of H and ²H; wherein R² is selected from the group consisting of Cl, Br, and I; and wherein R³ is selected from the group consisting of Cl, Br, and I.
 7. The labeled compound of claim 1: wherein R¹ is selected from the group consisting of Cl, Br, and I; wherein R² is selected from the group consisting of Cl, Br, and I; and wherein R³ is selected from the group consisting of Cl, Br, and I.
 8. A labeled compound having the structure:

wherein Z¹ is selected from the group consisting of H, alkyl, O-alkyl, S-alkyl, Cl, Br, and I; wherein Z² is selected from the group consisting of H, alkyl, O-alkyl, S-alkyl, Cl, Br, and I; wherein Z³ is selected from the group consisting of H, alkyl O-alkyl, S-alkyl, Cl, Br, and I; wherein Z⁴ is selected from the group consisting of H, alkyl, O-alkyl, S-alkyl, Cl, Br, and I; wherein Z⁴ is selected from the group consisting of H, alkyl, O-alkyl, S-alkyl, Cl, Br, and I; wherein X¹ is selected from the group consisting of S, O, SO and SO₂; wherein X² is selected from the group consisting of S, O, SO and SO₂. wherein R¹ is selected from the group consisting of H and ²H; wherein R² is selected from the group consisting of H and ²H; and wherein R³ is selected from the group consisting of aryls, alkyls and the following structure:

wherein Z⁶ is selected from the group consisting of H, alkyl, O-alkyl, S-alkyl, Cl, Br, and I; wherein Z⁷ is selected from the group consisting of H, alkyl, O-alkyl, S-alkyl, Cl, Br, and I; wherein Z⁸ is selected from the group consisting of H, alkyl, O-alkyl, S-alkyl, Cl, Br, and I; wherein Z⁹ is selected from the group consisting of H, alkyl, O-alkyl, S-alkyl, Cl, Br, and I, and wherein Z¹⁰ is selected from the group consisting of H, alkyl, O-alkyl, S-alkyl, Cl, Br, and I.
 9. The labeled compound of claim 8 wherein X¹ is S and X² is O.
 10. The labeled compound of claim 8 wherein X¹ is S and X² is S.
 11. The labeled compound of claim 8: wherein Z¹ is H; Z² is H; Z³ is H; Z⁴ is H; Z⁵ is H, X² is O; X¹ is SO; and wherein R³ is selected from the group consisting of aryls and alkyls.
 12. The labeled compound of claim 8: wherein Z¹ is H; 2 is H; Z³ is H; Z⁴ is H; Z⁵ is H, X² is O; X¹ is SO₂; and wherein R³ is selected from the group consisting of aryls and alkyls.
 13. The labeled compound of claim 8: wherein Z¹ is H; Z² is H; Z³ is H; Z⁴ is H; Z⁵ is H, X² is SO; X¹ is SO₂; and wherein R³ is selected from the group consisting of aryls and alkyls.
 14. The labeled compound of claim 8: wherein Z¹ is H; Z² is H; Z³ is H; Z⁴ is H; Z⁵ is H, X² is SO₂; X¹ is SO₂; and wherein R³ is selected from the group consisting of aryls and alkyls.
 15. The labeled compound of claim 8 wherein X¹ is SO; X² is O; and wherein R³ has the following structure:


16. The labeled compound of claim 8 wherein X¹ is SO; X² is SO; and wherein R³ has the following structure:


17. The labeled compound of claim 8 wherein X¹ is SO₂; X² is O; and wherein R³ has the following structure:


18. The labeled compound of claim 8 wherein X¹ is SO₂; X² is SO₂; and wherein R³ has the following structure:


19. A labeled compound having the structure:

wherein Bn is Benzyl and wherein X is selected from the group consisting of N and PhS.
 20. The labeled compound of claim 19 wherein the structure is:

wherein Ph is phenyl.
 21. The labeled compound of claim 19 wherein the structure is:


22. A labeled compound having the structure:


23. The labeled compound of claim 22 wherein the structure is: 